The overall goal of this program is to conduct investigations into the molecular mechanisms of lymphocyte activation in the hopes that this knowledge will be applicable to clinical issues related to the treatment of cancer. This goal will be addressed by the integrated efforts of three independent investigators who are attacking the scientific issues from a number of perspectives. The first project describes experiments investigating the molecular biology and biochemistry of how the CD45 tyrosine phosphatase functions to regulate signal transduction via the T cell and B cell antigen receptors and how CD45 may function also in signaling via CD4O. Experiments are described which probe the molecular basis of the relationship between CD45 and other cellular proteins and investigate the physiological relevance of these interactions. Additional experiments are described designed to identify phosphotyrosine containing proteins important in coupling signaling pathways after T cell receptor ligation. The second project of this proposal examines the structure/function relationships of CD4O as a signal transduction molecule expressed on the surface of B lymphocytes. Major focus of this project is to follow up on a novel observation suggesting that expression of CD4O on the surface of lymphocytes impacts significantly on signal transduction via another cell surface receptor, Fas. The third project examines the molecular biology and biochemistry of oligodeoxynucleotide- (ODN) mediated stimulation of B lymphocytes. These experiments are designed to understand better the signaling events which occur after ODN treatment of B cells and to determine what molecules in the B cells interact directly with these novel stimulatory agents. The work proposed by each project leader will be facilitated by an Administrative Core and a scientific core, the Signal Transduction Assay Core. The three projects and the two cores will take full advantage of the skills and experience of the individual project leaders and are mutually supportive; both intellectually and technically. As our laboratories have developed closer working relationships, we have discovered that our collaborative efforts are synergistic rather than merely additive. Formal integration of our efforts into this program will cement our collaborations and lead to increased productivity for each laboratory and a richer environment for our trainees.